Carboxylate Salt Bridge Mediated Enamine Catalysis: Expanded Michael Reaction Substrate Scope and Facile Access to Antidepressant (R)-Pristiq

We report broad guidance on how to catalyze enantioselective aldehyde additions to nitroalkene or maleimide Michael electrophiles in the presence of unprotected acidic spectator groups, e.g., carboxylic acids, acetamides, phenols, catechols, and maleimide NH groups. Remarkably, these L-threonine and L-serine potassium salt catalyzed reactions proceed even when the nucleophilic and electrophilic Michael partners simultaneously contain acidic spectator groups. These findings begin to address the historical non-compatibility of enantioselective catalytic reactions in the presence of acidic moieties and simultaneously encroach on the reaction capabilities normally associated with cellular environments. A carboxylate salt bridge, from the catalyst enabled enamine, to the Michael electrophile is thought to facilitate the expanded Michael substrate profile. A practical outcome of these endeavors is a new synthetic route to (R)-Pristiq, (-)-O-desmethylvenlafaxine, an antidepressant, in the highest yield known to date because no protecting groups are required.